Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments. However, their complexity presents synthetic challenges when generating analogs or quantities necessary for biological testing. One structural motif that creates a particular challenge is the enantioselective synthesis of carbocyclic structures containing quaternary stereocenters. In the current proposal, synthetic chemistry tools are described which will allow the efficient, enantioselective construction of carbocyclic structures with two quaternary stereocenters, vicinal quaternary- tertiary stereocenters and contiguous quaternary-tertiary-quaternary stereocenters. The synthetic tools will extend the recently developed Birch-Cope sequence in a valuable, new direction. Furthermore, the project describes a strategy to apply these tools to the enantioselective synthesis of trigonochinene D, a diterpene natural product with antimicrobial properties. The development of a synthesis of trigonochinene D and the tools to generate other complex molecules with antibiotic properties will assist in addressing the escalating crisis of antibiotic resistance. PUBLIC HEALTH RELEVANCE: Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments, especially antibiotic therapy. Trigonochinene D is a recently reported diterpene natural product which, with its unique chemical architecture and antibiotic activity, is representative of the riches found in natural product chemistry. The proposed project will develop synthetic chemistry tools to permit the efficient and specific synthesis of trigonochinene D, thereby facilitating its development as a new antibiotic treatment. With modern medicine facing a burgeoning crisis in antibiotic resistance, the tools developed here have the potential to facilitate important advances in the search for improved therapeutic treatments.